EPIPLASTCARCINOMA · Molecular mechanisms of epithelial plasticity and its involvement in carcinoma progression

Final Activity Report Summary - EPIPLASTCARCINOMA (Molecular mechanisms of epithelial plasticity and its involvement in carcinoma progression)

The aim of the project was to understand in molecular terms the signalling pathways and genes involved in epithelial pasticity, in particular EMT, determining their mechanisms of regulation and their function. The project has been extremely successful resulting in 92 articles in peer-reviewed journals, 14 book chapters, 9 articles submitted and 7 in preparation. There are also 6 patents pending. We have trained a total of 11 ESRs and 4 ERs. Of the ESRs, 6 will complete their PhDs either this year or next year, 3 left the network to work in other labs and 2 have just started PhDs this year. As well as 7 highly successful network meetings, we held a workshop on EMT in association with the EMT International Association, TEMTIA in Cracow in Poland in September 2007. There was an impressive list of internationally renowned speakers and the conference was very successful. It brought the EpiPlastCarcinoma network to the attention of the international EMT field. Finally as part of the career development for the ERs and ESRs we held a Scientific Careers Workshop, in London in June 2008, which was organised by an ER and ESR. It gave the ERs and ESRs good exposure to alternative careers other than scientific research. Research Highlights: One of the major signalling pathways involved in EMT is the TGF-beta pathway. We discovered a novel Smad pathway downstream of the TGF-beta receptors in epithelial cells, which is likely to be important for the tumour promoting activities of TGF-beta. We also defined the role of the different Smads in the tumour promoting versus tumour suppressive functions of TGF-beta. Furthermore, we identified an E3 ubiquitin ligase and a deubiquitating enzyme (Ectodermin/TIF1 gamma and FAM respectively) as key new regulators of the TGF-beta pathway. We investigated the role of TGF-beta signalling in cancer and found a strong correlation between cells which migrate in vivo as individual cells and the presence of TGF-beta signalling. We found direct evidence for localised, transient and reversible changes in TGF-beta signalling driving changes in cell behaviour during metastatic dissemination. We have also discovered a novel role of p53 and p63 in tumourigenesis. We found that two common oncogenic lesions, mutant-p53 and Ras, selected for in early neoplasms to promote growth and survival, also promote metastasis by a TGF-beta-dependent inhibition of p63 function. A major goal was to identify new regulators of EMT and to determine if they could be used as diagnostic or prognostic markers in human cancer. Importantly, we have now identified a number of new regulators of EMT, including HMGA2, Notch, Meox2, PDGF signalling, ILEI, AnnexinA2, CREG and LOXL2. These have been extensively characterised. The expression of some of these has been studied now in human cancers. Most significantly we found that expression of PDGFR alpha and beta proteins correlated with invasive behaviour in human mammary carcinomas. Moreover, ILEI is overexpressed and/or altered in intracellular localisation in a number of human tumours and this correlates with invasion/EMT and metastasis. Analysis of LOXL2 and Snail1 expression by IHC in 250 laryngeal squamous cell carcinomas (LHNSC) showed that LOXL2 overexpression is associated to decreased overall and disease-free survival, while Snail1 expression associates to local recurrence. These results identified LOXL2 as a new poor prognosis marker of LHNSC. Finally we have characterised a novel inhibitor of TGF-beta signalling, GW788388, which has the potential to be of therapeutic use in the treatment of patients with renal fibrosis.

Data: CORDIS, © European Union